Cell Signaling

Cell signaling is the system of signal transduction by which communication between and inside cells, and their response to external stimuli, is carried out, requiring a directional transmission across membranes in which a primary messenger docks onto an external receptor and the signal is internalized in the form of a released second messenger that starts a cascade of events controlling all functions of the living cell. ^[1] Signaling is inherently dynamic, and its behavior reflects features such as the role of stochasticity in producing diversity, feedback interactions that can synchronize multiple signal transduction pathways, scaffolding proteins that control signaling feedback, and frequency-responsive transcriptional regulation. ^[2]

Heterotrimeric G-proteins relay information from G-protein-coupled receptors on the plasma membrane to the inside of cells to regulate diverse biochemical functions, and depending on the targeted cell types, tissues, and organs, these signals modulate diverse physiological functions. ^[3] Ras proteins act as a branchpoint in signal transduction because they orchestrate the activity of multiple signaling pathways to regulate diverse cellular functions including cell growth, differentiation, and apoptosis. ^[4] Many cellular signaling processes are governed by endocytosis, through the internalization of plasma membrane receptors, which also enables the formation of endosome-specific signal transduction complexes. ^[5] At moderate concentrations, nitric oxide, superoxide anion, and related reactive oxygen species play an important role as regulatory mediators in signaling processes, and in a given signaling protein oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. ^[6] Signaling is further tuned by post-translational lipid modification, as reversible S-palmitoylation of protein cysteine residues alters protein stability, conformation, localization, membrane association, and interaction with other effectors. ^[7]

Aging involves progressive changes in free-radical-mediated regulatory processes that result in altered gene expression, in addition to radical-mediated oxidative damage. ^[6] Cells assess mitochondrial function and activate the mitochondrial unfolded protein response through signal transduction mechanisms, and recent insights into its regulation have uncovered important and complex links to ageing and ageing-associated diseases. ^[8] Mitochondria are now viewed not solely as ATP-generating organelles but as key regulators of cellular signaling that shape physiologic aging, with age-related loss of mitochondrial signaling and function linked to important physiologic changes of aging. ^[9] Cellular metabolism plays a significant role in regulating the various signaling processes involved in cell senescence, whose accumulation in tissues during aging promotes age-related diseases and limits health span. ^[10]

The integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes, and pharmaceutical modulation of its cytoprotective activity is suggested to be beneficial for human health across a broad range of noncommunicable diseases. ^[11] The preliminary phases of the mitochondrial integrated stress response can provoke an adaptive stress response that antagonizes age-related diseases and promotes longevity, making it a potential therapeutic target. ^[12] Mild inhibition of mitochondrial respiratory function with drugs like metformin promotes health span, opening new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging. ^[9]